3-chloro-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)propanamide | 1233953-82-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 3-chloro-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)propanamide
• 英文别名: N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-chloropropanamide；3-chloro-N-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]propanamide
• CAS: 1233953-82-6
• 化学式: C₂₇H₂₃Cl₂N₅O₃
• 分子量: 536.417
• InChiKey: YVSGPSVBYNCYKV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  37
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  吗啉 、 3-chloro-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)propanamide 在 potassium iodide 、 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 9.25h， 以74%的产率得到N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)-3-morpholinopropanamide
  参考文献：
  名称：

  Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

  摘要：

  Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

  DOI：

  10.1021/jm201507x
• 作为产物：
  描述：

  N-（2-羟基-4-硝基苯基）乙酰胺 在 盐酸 、 palladium on activated charcoal 、 氢气 、 吡啶盐酸盐 、 potassium carbonate 、 三氯氧磷 作用下， 以 四氢呋喃 、 diphenyl ether-biphenyl eutectic 、 二乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 、 异丙醇 、 甲苯 为溶剂， 反应 5.0h， 生成 3-chloro-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)anilino)-3-cyano-7-ethoxyquinolin-6-yl)propanamide
  参考文献：
  名称：

  Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

  摘要：

  Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.

  DOI：

  10.1021/jm201507x

文献信息

• [EN] IRREVERSIBLE EGFR INHIBITOR COMPOUNDS WITH ANTIPROLIFERATIVE ACTIVITY<br/>[FR] COMPOSÉS INHIBITEURS IRRÉVERSIBLES DE L'EGFR DOTÉS D'UNE ACTIVITÉ ANTIPROLIFÉRATIVE
  申请人：UNIV PARMA

  公开号：WO2010076764A1

  公开（公告）日：2010-07-08

  The invention concerns a derivative of Formule (VII) wherein R27, R28 are, independently of each other, hydrogen, (C1-C6)alkyl, (CH2)n- COOR33, (CH2)n-CONR33R34, (CH2)n-NR33R34 or (CH2)n-morpholine; or NR27R28 is — N N-R27 selected from morpholine, piperidine and Formula (VIII), where R33, R34 are, independently, hydrogen or (C1-C6)alkyl; R29 is hydrogen or (C1-C6)alkyl; R30 is hydrogen or -OR35, where R35 is (C1-C6)alkyl, (CH2)n-NR33R34 or (CH2)n-piperidine or (CH2)n-morpholine, where R33, R34 are, independently, hydrogen or (C1-C6)alkyl; Y is a nitrogen atom or a carbon atom substituted by a cyano group; R31 and R32 are, independently of each other, hydrogen, bromine, chlorine, fluorine, ethinyl or methyl; X is hydrogen, bromine, chlorine, fluorine or -O(CH2)n-Q; Q is an aryl or heteroaryl group, optionally substituted by one or more substituents selected, independently of each other, from hydrogen, chlorine, fluorine, the CF3 radical or - NO2; n is a whole number selected from 0, 1, 2, 3, 4, 5, or 6. The derivatives of the invention are used as irreversible EGFR inhibitors with antiproliferative activity.

  本发明涉及Formule（VII）的衍生物，其中R27，R28分别独立地是氢，（C1-C6）烷基，（CH2）n- COOR33，（ ）n-CONR33R34，（ ）n-NR33R34或（ ）n-吗啉；或NR27R28是所选自吗啉，哌啶和Formula（VIII）的— N N-R27，其中R33，R34独立地是氢或（C1-C6）烷基；R29是氢或（C1-C6）烷基；R30是氢或-OR35，其中R35是（C1-C6）烷基，（ ）n-NR33R34或（ ）n-哌啶或（ ）n-吗啉，其中R33，R34独立地是氢或（C1-C6）烷基；Y是氮原子或被氰基取代的碳原子；R31和R32独立地是氢，溴，氯，氟，乙炔或甲基；X是氢，溴，氯，氟或-O（ ）n-Q；Q是芳基或杂环芳基，可选地由一个或多个取代基取代，所选自氢，氯，氟，三氟甲基基团或-NO2；n是选自0，1，2，3，4，5或6的整数。本发明的衍生物被用作具有抗增殖活性的不可逆EGFR抑制剂。